Facile discovery of surrogate cytokine agonists

Cell. 2022 Apr 14;185(8):1414-1430.e19. doi: 10.1016/j.cell.2022.02.025. Epub 2022 Mar 23.


Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This "cytokine med-chem" approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems.

Keywords: SARS-CoV-2; VHH; bispecific antibodies; cell signaling; cytokine engineering; interferon; interleukin-10; interleukin-2; scFv.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19*
  • Cytokines*
  • Humans
  • Interleukin-2 / pharmacology
  • Killer Cells, Natural
  • Ligands
  • Receptors, Interleukin-10
  • SARS-CoV-2


  • Cytokines
  • Interleukin-2
  • Ligands
  • Receptors, Interleukin-10